Arsenic trioxide (As2O3) is a main ingredient in Pishuang, a traditional Chinese medicine. The Chinese people began to use arsenic-containing medication to treat a wide variety of diseases as early as 2400 years ago. In early 1970s, scholars in Harbin Medical University tried to treat leukemia using Ailing-I injection solution. In August 1996 Science headlined Old Drug New Application highlighting effectiveness of As2O3 in treating acute promyelocytic leukemia used by Chinese physicians. From then on, arsenic-containing preparations became one of the hot spots in research on tumor treatment. Biological characteristics of arsenic-containing preparations fall into two aspects. On one hand, arsenic is a highly toxic material building up in body, combining with thiol proteins, affecting important enzyme system, undermining cell metabolism and inducing tumors. However, arsenic itself is not a carcinogen. On the other hand, arsenic is extensively distributed in nature while residing also in human body with a total amount of 14-21 mg, acting as an indispensable element. Certain amount of arsenic is able to stimulate hemopoiesis and promote cell growth. Arsenic-containing preparations enjoy many advantages in treating leukemia without inhibition of bone marrow, causing DIC, severe infection or bleeding. In addition, these preparations are able to penetrate blood-brain barrier very effective in fighting against solid tumors such as primary liver cancer, boasting merits including highly selective for tumor cells and little side and toxic effects.
Researches conducted by experts, both home and abroad, reveal that As2O3 can significantly inhibit solid tumors including liver cancer, stomach cancer, pancreas cancer, esophagus cancer, colon cancer, lung cancer, Ehrlich Ascites cancer, neuroblastoma, cervical carcinoma, ovary cancer and breast cancer. Domestic research institutes have reported safety and effectiveness of As2O3 in treating APL. Currently, American researchers are conducting a multi-centered research on APL trying to probe safety and effectiveness of As2O3 in treatment of APL. In 1999 the SDA approved As2O3 a National Class II new drug, formally produced and marketed by Harbin Yida Pharmaceuticals. In September 2000, the FDA also approved American Cell Therapeutic Company to produce and market As2O3 injection acting as a second-line drug for treatment of recurrent APL. At present, many research institutes, both home and abroad, are conducting clinical trials on treating multiple myeloma, malignant lymphoma, MDS and other malignant tumors.
Researches reveal that As2O3 takes effects as followings:
(1) Arsenic-containing preparations are cytotoxic (protoplasmic poison) inhibiting cell propagation, suppressing nuclear acid metabolism in tumor cells, interfering synthesis of DNA and RNA, halting protein synthesis, blocking mitosis of cells thus killing tumor cells;
(2) Arsenic-containing preparations are able to induce apoptosis. They combine thiol-base (—SH) containing materials, affecting trans-membrane potential of mitochondria, down regulating ratio of Bcl-2/Bax, and activating apoptosis effectors molecule caspase 3, 8, Fas and Fas-L, and increasing free Ca2+ in the cells;
(3) Arsenic-containing preparations can induce cell differentiation. In anti-leukemia researches these preparations presented effect on inducing maturation and differentiation of promyelocyte, however, their effect on solid is still unreported; and
(4) Arsenic-containing preparations help induce apoptosis of endothelial cells of blood vessels and inhibit angiogenesis. Yu Zhiyong et al. (Arsenic trioxide induces apoptosis in HUVECs and inhibits angiogenesis in CAM, Medical Journal of the Chinese People's Armed Police Forces, 2004(1)) conducted researches on As2O3's effect on inducing apoptosis and inhibiting angiogenesis of endothelial cells of blood vessels of human umbilical vein, revealing As2O3 is able to inhibit growth of HUVECs, induce cell apoptosis and inhibit angiogenesis.
Huang Shouguo et al. (Comparative study on the effects of arsenic trioxide and cisplatin on the ovarian carcinoma cell strain 3AO in vitro, Acta Academiae Medicinae Shandong, 2002(2)) compared effect of As2O3with Cisplatin onto human ovary cancer strain 3AO, revealing that As2O3 is able to block S phase and induce typical apoptosis in morphology. Compared with cDDP, As2O3 is more effective in inhibiting growth, inducing apoptosis and blocking S phase of 3AO. Wei Guoqing et al. (Journal of Practical Oncology, 2006(1)) conducted experiments probing effect of a combination of daunorubicin (DNR) , Ara-C, Homoharringtonine (H) and vincristine (VCR) onto in vitro cytotoxicity of acute non-APL (ANPL), revealing that As2O3is free from cross drug resistance with Ara-C, Homoharringtonine and VCR, but partly has cross drug resistance with DNR. Thus As2O3 can be used to form a new chemotherapy cohort with DNR and/or VCR treating naive or recurrent ANPL. Zhang Daxi et al. (Radiation enhancement and induced apoptosis in ovarian cancer cells by arsenic trioxide, Chinese Journal of Radiation Oncology, 2003(1)) probed effect of a combination of As2O3 with radiation therapy onto human ovary cancer cell strain SKOV3, finding that As2O3 within normal clinical dosage range can enhance effect of the radiation therapy in routine graded dosages.
Zhu Hongli et al. (The Expression of Fas, FasL and Bcl-2 on RMA Cells during the Process of Apoptosis Induced by Chemotherapeutic Drugs, Journal of Experimental Hematology, 2002(1)) probed effect of a combination of chemotherapeutic VP 16, As2O3, ATRA with cytokines IL2, IL6 and GM CSF onto apoptosis of mouse T lymphoma, finding the combination is able to induce apoptosis with lower drug concentration and ahead time of apoptosis, showing a synergistic effect, and providing experimental data for treatment of malignant lymphoma using chemotherapeutic cohort. Su Ying et al. (Effect of Arsenic Trioxide Combined with Interferon in K562 and K562/ADM Cell Lines, Journal of Fujian Medical University, 2003(2)) studied effect of a combination of As2O3 and interferon onto drug-resistance cell strains K562 and K562/ADM, indicating As2O3 is able to inhibit expression of Bcl-2 protein of K562 and K562/ADM, induce apoptosis and the effect has a dosage-time effect. A cohort of IFN α-2b and As2O3 is able to enhance effect onto K562, however less effective to enhance effect onto K562/ADM, indicating As2O3 is able to inhibit K562 and K562/ADM's expression of GST-πand Bcl-2 proteins and induce apoptosis, however futile to expression of P-gp protein. IFN α-2b can enhance the above effect. Song Tiefang et al. (Chinese Journal of Oncology, 2003(3)) conducted researches on inhibitive effect of a combination of As2O3 with TNF onto human liver cancer cell strain HepG2, revealing As2O3 and TNF are synergistic each other, and the combination is more effective than any individual in the combination in inducing apoptosis.
Currently, most arsenic-containing medications are administered via non-intestinal routes, including in vein injection, in muscle injection, local injection, in cavity administration, drug-pump administration and intervention administration. Zheng Mingyou et al. (Effects of Arsenic Trioxide by Transcatheter Arterial Chemoembolization on Rabbits with Hepatic Vx-2 Carcinoma, Cancer Research On Prevention and Treatment, 2004(12)) probed inhibition to rabbit Vx2 hepatic transplantation carcinoma of As2O3 via hepatic artery catheter perfusion, revealing it is significantly effective in treating tumors showing a dose dependent relation, and As2O3 induces apoptosis via up regulating expression of bax gene. Qi Xiaojun et al. (Chinese Journal of Postgraduates of Medicine, 2006(17)) studied effect of a combination of injection of As2O3 via B-ultrasound-guided percutaneous puncture with via-hepatic-artery chemotherapy embolism onto liver suffering from primary cancer, finding the combination is superior to using via-hepatic-artery chemotherapy embolism exclusively. Zhu Anlong et al. (The effect and mechanism of arsenic trioxide on hepatocellular carcinoma, Chinese Journal of Surgery, 2005(1)) studied chemotherapeutic value of As2O3 for primary liver cancer as well as its best administration route. They punctured 17 patients unsuitable for surgical operation via femoral artery or axillary artery, identifying location and range of the tumors by using hepatic arteriography DSA. They imbedded perfusion devices (micro-pump) under skin for left, right and proper hepatic artery, linking the micro-pump to a micro-injector. The pump-injected As2O3 was administered to the cancerous areas for consecutive five days at a dosage of 20 mg/d. After having undergone 4 therapeutic courses, 6 cancerous lesions shrank the size by 50% plus and no new lesions occurred (PR=35.2%); and 8 lesions shrank by 10-49% (overall effectiveness rate was 41.1%), one lesion did not change, and 2 lesions boomed by 25% plus. No explicit side effects took place. The results indicate that administration of As2O3 to local lesions is effective for solid tumors enjoying advantages such little side effects and explicit effect.
Commonly seen side effects include digestive reactions such as dry mouth, bitter mouth, fullness of abdomen, skin itching and rash, rarely seen side effects include urinary reactions such as edema in face and lower limbs and loss of leukocytes. Disorders in blood coagulation are rare. Further researches are needed for the best dosage, combination and therapeutic course of use of As2O3. Other issues should also be clarified such as kinds of solid tumors besides APL that are sensitive to As2O3, safety of As2O3, whether or not it will cause secondary tumor, induce drug resistance and problems caused by combination with other drugs, etc.
The therapy method of arterial embolism is to inject embolus to micro-arteries causing mechanical blocking and inhibiting tumor growth. In 1981 Kato debuted this therapy method combining chemotherapeutic drugs with embolism materials treating malignant tumors unsuitable for surgical operations. In recent years this method has been applied to treat liver cancer, renal cancer, tumors in pelvis and head and neck showing effective result. However, this method suffers from a high relapse rate.
Microsphere preparations are particles with a diameter of 20-1000 μm that contain certain drugs and are made with proper auxiliary materials. Effectiveness of microsphere for embolism purpose depends on diameter, degrading speed of skeleton of the microsphere, drug-carrying speed and drug release speed. The drug-containing microsphere preparations can block micro-vessels that supply blood to the cancerous lesions releasing anti-tumor drugs and killing cancerous cells, enabling the drugs to be targeted and controllable. This kind of method for drug administration is able to improve drug distribution in vivo and pharmacokinetic features, increase bioavailability of drugs, improving treatment effect and alleviate toxic or side effects.
Microsphere preparations for arterial embolism should have characteristics as the followings: powerful enough to embolism, strong mechanically and stable physically and chemically, the drug can be released slowly and persistently, maintaining a therapeutic concentration in the targeted areas; the drug carrier can be eroded by the receiver, and is biocompatible, free from antigenicity, and free from harms to body even lingering around the targeted areas for a long time.
Thus some topics for this research subject includes: how to prepare microsphere embolus containing As2O3 by using degradable materials, how to apply the microsphere embolus to treatment of tumors locally, how to prevent As2O3 encapsulated by degradable materials from leaking, and how to prevent wet microsphere that is water soluble from leaking.
Microsphere preparations are made with certain drugs and auxiliary materials using micro-encapsulation technology. Administration of drugs in the form of microsphere helps the drugs to be site targeted and release controllable, this kind of method for drug administration is able to improve drug distribution in vivo and pharmacokinetic features, increase bioavailability of drugs, improving treatment effect and alleviate toxic or side effects. Chemotherapeutic-drug-containing Microspheres via arterial embolism can cluster in arterial vessels around the lesion blocking blood supply to the lesion and releasing drug persistently, effectively inducing apoptosis and causing ischemic and anoxia and death of cancerous cells. Currently the most frequently used microsphere preparation is with As2O3, which can increase its concentration immediately after in vein administration, spreading to tissues around the tumor lesion causing side effects including digestive symptoms, peripheral neuritis, dry skin and pigmentation, even renal impairment, pleural collection and ascites. To overcome the shortcomings, the present disclosure creates the sodium alginate microsphere vascular embolus containing water-soluble drug, enabling some special carriers to encapsulate water-soluble drugs using some special physical and chemical processes. In addition, the microsphere preparations will be administered locally or via intervention route reducing drug dosage, alleviating side effects and improving therapeutic effect.